Estrogen sulfotransferase (EST or SULT1E1) is a phase II conjugating enzyme best known for its activity in sulfonating and deactivating estrogens, an anti-inflammatory hormone. This is because sulfonated estrogens fail to bind to and activate the estrogen receptor. EST has been shown to be transcriptionally regulated by nuclear receptors. However, it is unclear whether and how EST is regulated by inflammatory stimuli and what is the consequence of inflammation responsive regulation of EST. The estrogen homeostasis is tightly regulated by balanced synthesis and metabolism of estrogens. A critical metabolic pathway to deactivate estrogens is through EST-mediated sulfation. However, it has not been tested whether the expression and regulation of EST affect the host's sensitivity to inflammatory stimuli. Our preliminary results showed that: 1) Treatment of mice with bacterial lipopolysaccharide (LPS) or subjected mice to the cecal ligation and puncture (CLP) model of sepsis induced the expression and activity of EST specifically in the liver in time- and dose-dependent manner; 2) Depletion of liver Kupffer cells attenuated the EST induction by LPS; 3) The EST induction in LPS-treated mice was associated with an inhibition of estrogen-induced uterine epithelial proliferation and estrogen responsive gene expression, as well as a decreased circulating level of estradiol; 4) The LPS induction of EST appeared to be nuclear receptor- independent. In contrast, the CLP induction of EST was abolished in Toll-like receptor 4 knockout (TLR4-/-) mice; 5) EST is a potential NF-?B target gene, and several putative NF-kB binding sites have been predicted in the EST gene promoter; 6) The inflammatory regulation of EST was conserved in male mice, as well as in human liver cells; 7) EST-/- mice were attenuated from an LPS-responsive inflammatory response, likely due to increased estrogen activities. Based on these observations, we hypothesize that EST is subject to the regulation by inflammatory stimuli; and reciprocally, the expression and regulation of EST influence the host's sensitivity to inflammatory stimuli. Specifically, we hypothesize that: 1) LPS and CLP induce the expression of EST, and consequently deprive estrogens; 2) TLR4 is required for the inflammatory responsive regulation of EST, and EST is a transcriptional target of NF-kB; and 3) EST ablation attenuates mice from, whereas transgenic overexpression of EST in the liver sensitizes mice to, LPS- and CLP-induced inflammatory responses. We propose three specific aims to test our hypotheses: 1) To determine whether the inflammatory stimuli deprive estrogens in an EST-dependent manner; 2) To determine the molecular mechanism by which the inflammatory stimuli regulate the expression of EST; and 3) To determine whether EST ablation attenuates mice from, whereas transgenic overexpression of EST in the liver sensitizes mice to, LPS- and CLP-induced inflammatory response. To our knowledge, this study represents the first attempt to evaluate the regulation of EST in response to inflammatory stimuli and the implications of this regulation in estrogen homeostasis. The proposed study is of medical significance, especially in women's health. We reason that the reciprocal regulation of inflammation and EST may represent a yet to be explored mechanism of endocrine regulation of inflammation. Elucidation of this mechanism may provide a novel therapeutic target for the prevention and treatment of inflammation related diseases.